Process of making long chain intermediates



Patented May 15,;1

UNlTEDii "STATES PATENT orrlce I rnocass F Lee Irvin Smith, Minneapolis,Minn, and George F. Bouault, Whiting, Ind., as llnors to Regents of TheUniversity of Minnesota, Minneapolis,

Minn., a corporation 0! Minnesota No Drawing. Application March 11,1944,

' Serial lfIo. 526,127

- some; (01. 260-451) The present invention relates to the production orlong chain aliphatic compounds, and more particularly long chainaliphatic compounds having recurring isoprene units, 7

which are especially adapted for the synthesis of tocopherolandItocopherol-like compounds.

The synthesis in quantity of long chain compounds, I particularly thosecarrying substituents on the chain, is a matter ofconsiderable-dlmculty.

The number of steps is usually large, and only too often some one Ormore steps in the synthesis give very poor yields 'so that, from thepoint of view of quantity production of these complicated compounds,most of the known syntheses are not satisfactory. In the synthesis ofthese" complicated compounds the chances'ofi commercial success are muchbetter when larger fra ments are combined to produce the desiredcompound.

In the present invention advantage is taken of this fact by combiningtwo fragments of considerable size in a particular manner such that by afew subsequent reactions it is possible'to arrive at satisfactory yieldsof the desired complicated aliphatic compound; To this end the 1invention contemplates thereaction of 2,6-di-" 'methylheptanoic acidwith p-cresol followed by" a series of reactions resulting in theproduction of the aliphatic halide RX where R is It is therefore anobject of the present invention to provide 'a process of preparing:complicated long chain aliphatic compounds with substituents on thechain, and P rticularly to provide a method of making a compound havingthe structure H[CH2CH(CH:) CHzCHzlaCHzX.

It is another object of the invention to prepare such compounds insatisfactory yields by combining large fragments of such compounds andfurther processing the combination, allin a prescribed manner, to yieldthe desired product.

It is a further object to prepare such compounds from readily'availablenaturally occurring raw materials. Other objects of the invention willappear from the following description of the invention.

In the I copending application of the present inventors filed Of evendate herewith and entitled "Method of making aliphatic intermediates,"it was shown that certain naturally occurringaliphatic compounds such ascitronellol can 7 be converted into compounds of the type RiCOX,

where R1 is (CH3) 2CHCH2CH2CH2CH (CH3) and X is halogen, OH or other'group capable of esterifying an alcoholic OH group. In thepresentinvention, the two potential isoprene" groups of thisdimethylheptanoic acid are employed in conjunction with the potentiallsoprene group j of p-cresol to prepare the halide,4,8,12-trimethyltridecyl bromide, referred to above. 1 The generalprocedure followed in carrying out the invention is illustrated by thefollowing reactions: (R1 is 6-methylheptyl-2) mcoo: H i

i H H,

H OH H H CH R H Catalytic cam, Reduce e- 4-- H; H: dehydration H: H,with E H CH3 H CH5 \Oxidize OH COGH R l Esterify with XIII m-g EtOH andreduce H; H! with Zn H01 C (JHa Convert OH to Br XVI For esterificationof the p-cresol other forms of the acid group may be used but the acylhalide was found highly desirable in view of the fact that the esterVII, so formed, is in the preferred form of the process subjected to aFries rearrangement with AlCla without isolation of the ester. It wasfound that the acyl cresol IX, may be reduced practically quantitativelyto the alkyl cyclohexanol X, by a two stage hydrogenation under1800-2500 lbs. pressure in the presence of Raney nickel, first at 175 C-and then at 225 C. The reduction may be carried out in the absence of asolvent or in the presence of alcohol but unusually prolonged reactiontimes and elevated temperatures should be avoided to preventhydrogenolysis and production of the disubstituted cyclohexane.

In the dehydration step two paths were possible. One of these wouldproduce 5-methyl-3- nonyl-l-cyclohexene, a product useless for ourpurpose. The second path would produce 5- methyl-l-nonyl-l-cyclohexene(XII) the compound desired in the present synthesis. It was discoveredthat the dehydration could be caused to follow the second path and'thepresent synthesis was thus feasible.

The cyclohexene XII may then be oxidized to break the ring and form theketo acid XIII. The action of ozone on the cyclohexene in ethyl bromidefollowed by the decomposition of the resultant ozonide by' the action ofhydrogen peroxide in acetic acid was found to produce the keto acid in90% yield.

It was found that the keto acid XIII could be suitably reduced to thesaturated acid and esterified to the ester XIV, this being accomplishedsimultaneously. for example, by a Clemmensen reduction in the presenceof alcohol in yields of about 65%. This ester, by further and moredrastic reduction, as for example hydrogenation at 250 C. under apressure of 2800 lbs. in the presence of copper chromite catalyst, wasconverted into the alcohol XV in yields of about 85%. The

asraaee H H a.

XIV

CHQCHQR] Reduce catelytlcally with hydrogen in a bomb CHaOH CHaCHzRx68.6 g. of freshly distilled p-cresol were placed in a one-liter,three-neck flask equipped with a .Hershberg stirrer, a dropping funneland an outlet tube. 75.5 g. aluminum chloride were added to the cresoland the mixture was heated in an oil bath for two hours at 130-140 C. 93g. of 2,6-

dimethylheptanoyl chloride were then added over bromide XVI was producedfrom the alcohol by the action of dry hydrogen bromide at C. The bromideso produced was converted to a Grignard reagent and this was then usedto proa 10minute period to the vigorously stirred mixture. Thetemperature was maintained at C. and stirring was continued for a periodof one and one-quarter hours. The cooled mixture was decomposed by theaction of 400 cc. of boiling hydrochloric acid (18%). The oil wasremoved and fractionated. After a forerun of 5.3 g. having a boilingpoint of 104 C. at 3 mm. was removed, 90.8 g. (69% yield) of the acylcresol IX having a boiling point of 144 C. at 3 mm. were obtained.

79.5 g. of the above acyl cresol, 85 cc. of'dry I ethanol and 21 g. of aRaney nickel catalyst were mixed and heated at-195 C. for two hoursunder a hydrogen pressure of 17003700 lbs. The cooled mixture wasfiltered and the alcohol was removed from the filtrate by distillationunder slightly reduced pressure. The residue was heated with 9 g. of aRaney nickel catalyst for four hours at C. under a hydrogen pressure of1700-2400 lbs. The catalyst was removed and the product was distilled.74.0 g. (96% yield) of the cyclohexanol X having a boiling point of 133C. at 3 mm. were obtained.

22.3 g. of this cyclohexanol together with 2.3 g.

of p-toluenesulfonic acid were heated for fifteen minutes at C. in ametal bath. The cooled mixture was dissolved in ether and the etheralsolution was washed successively with water, sodium hydroxide and againwith water. The solvent was removed and the residue was distilled toyield 18g. (87%) of the cyclohexene-XII hav:. ing a boiling point of 141C. at mm. pressure. 13.9 g. of the cyclohe'xene-XII, dissolved in 300ethyl bromide was removed by distillation on ,1

steam bath. cc. of 30% hydrogen peroxide were added and the mixture washeated for two hours on a steam bath. The solution was diluted with 600cc. of water and extracted with two 100 cc. portions of ether. Thecombined extracts were washed withwater, acidified ferrous. sulfatesolution (2%) and again withwater. The solvent was removed and theproduct was distilled to yield 15.6 g. (92%) or the keto acid- XIII,having a boiling point of 170 C. at 4 mm. pressure.

4.8 g. of this keto acid were dissolved in 110 cc. dry ethanol which hadbeen saturated with hydrogen chloride. The solution was refluxed forforty hours with 100 g. of amalgamated zinc. Twice during this period,hydrogen chloride was passed into the mixture until it was saturated.The mixture was poured-into 600 cc.-.of water and the oil was removed,washed with water, and distilled. 3.6 g. (71% yield) of the ester XIV,ethyl 4,8,1z-trimethyltridecanoate, having a boilcorrespondlngalcohol,and converting the alcohol to the 1-halo-4,8,l2-trimethyltridecane.

reducing and esterityingthe keto acid to a 43,12 ;l

trimethyltridecanoate, reducing the ester to the 2. Process of producing1.-bromo-4,8,l2-tri methyltridecane which comprises esterifying pcresolby means of acompol d having a 2,6-di-.

V methylheptanoyl group,rearranging the ester to the'ortho acylcresol, 2[2 ',6'-dimethylheptanyoll- 4 -inethylphen'o'l, reducing said acylcresolto the corresponding cyclohexanolp2['2,6-dimethylheptyll-4-methylcyclohexanol, dehydrating said,

cyclohexanol to the cyclohexene,5-methyl-ll2',6'-dimethylheptyll-1-cyclohexene, oxidizing 1 saidcyclohexene to the corresponding keto acid,

4,8,l2-trirn'ethyl-fi ketotridecandic acid, reducing and esterifying theketoacid toa 4,8,l2-trirhethyltridecanoate, reducingthe ester w thecorresponding alcohol, and converting the alcohol to the1-bromo-4,8,lZ-trimethyltridecane.

3. Process oi producing 1-halo-4,8,l2-trimethyltridecane which comprisesesterifying pcresol by means of a 2,6-dimethylheptanyol halide,rearranging the esterto the'orthoacyl I cresol, 2[2,6-dimethylheptanoyll4 methyl phenol, reducing .saldacylcresol to the correspondingcyclohexanol, 2[2',6-dimeth.ylheptylling point of 160 C. at 3vmm.;pressure were ob-' tained.

I The ester XIV in the amount of 10.55v g. was heated with 2.0 g. ofcopper chromite catalyst at- 250 C. for five hours under a hydrogenpressure of 2800 lbs. The mixturewas washed out of the bombwith 50 cc.alcohol, the solution was flitered, and the alcohol was distilled fromthe n1- 1 trate under 15 mm. pressure. The. yield was 7.4

g. (85%) 01 alcohol XV, 4,8,12-trimethyl-1-tri decanol, having aboilingpoint 01140? C.-at 3 mm. pressure.

4-methylcyclohexan'ol, dehydrating said cyclohexanol to'the cyclonexene,5-methy'1-1-'[2,6.- dimethylheptyll-1-cyclohexene, oxidizing saidcyclohe'xene to. the corresponding keto acid,

4,8,12-trimethyl-6-ketotridecanoic acid, reducing The alcohol XV wasconverted-to bromide as follows: Dry hydrogen bromide (froma 1 mm.orifice, 4 bubbleslper second) was passedthrough 7.7 g. of the alcoholXV at 120 C. for one and onequarter hours. sively with 4 cc. sulfuricacid, cc. aqueous methanol, and water and dried over calcium chlo-. rideand fractionated. 5.5 g. (57% yield) of bromide XVI,1-bromo-4,8,12-trimethyltridecane, having a boiling point of 135 C. at2-3 mm. pressure were obtained. Thebromide had an index of refraction11. 1.4560. v

, It is to be understood that the above detailed steps areillustrativeonly and while the invention is preferably carried out in this manner,a-

other ways of effecting the individual steps in the sequence may beemployed without departing from the plan of the invention and withoutdeparting from the spirit of the invention, as so forth in the appendedclaims. 7 i

What we claim is: i 1. Process of producing methyltridecane whichcomprises esterifying pcresol by means of a compound having a 2,6-'

dimethylheptanoyl group, rearranging the ester- The product was washedsucces-I and esterifying the keto acid to a4,8,12-trimethyltridecanoate, reducin the ester to the correspondingalcohol, and converting the alcohol to the 1-halo-4,8,12-trimethyltridecane.

LJProcess. of producing 1-ha10 -4, 8,12- .-trirnethyltridecahewhichcomprises esterifying pcresol by means of a compound having a2,6-dimethylheptanoyl group, rearranging the ester to the orthoacylcresol, 2 [2 ,6 -dimethylheptanoyll 4-methylphenol, reducing saidacylcresol to the corresponding cyclohexanol, 2[2 ,6-dimethyle heptyll-4-methylcyclohexanol,; dehydrating said .cyclohexanoljto thecyclohexene, 5-methyl-l- [2. ,6"-dimethylheptyl] -1-cyclohexene,oxidizing saidcyclohexene to the corresponding keto acid,i,8,1zetrimethyl-fieketotridecanoic 'acid,-'reducing' 56 and esterifyingthe keto'acicl.to'ethyl'1;8,12-triv-methyltridecanoate, reducing theestersto the corresponding alcohol, and converting-thealcohol to thel-halor 1,8,12 trimethyltridecane;

cr'es'ol 2L2,6'-dimethylheptanoyllirl-methylphenol, reducing saidacylcresolto the. corresponding cyclohexanol, I '2 EZZS -dimethyIheptyIl4-methyl cyclohexanol, dehydrating'said cyclohexanolin,

the presenceof p-toluenesulionic acid as a catalyst to the cyclohexene,-5-methyl-1- [2,6-dimethylheptyl-l l-cyclohexene, ozonizing said cy-'clohexene-to the'corresponding keto acid, 4,8,12-

' .trimethyl -S-ketotridecanoic acid, reducing. and

to the ortho acylcresol, 2[2',6-dimethylhe1:rt'-

anoyll -4-methylphenol, reducing said acylcresol to the correspondingcyclohexanol; 2[2',6'-dimethylheptyll -4-methylcyclohexanol,'dehydratesterifying the keto acidto a 4,8,l2-trilmethyltridecanoate,catalytically reducing the esterunder;

pressure to the corresponding alcohol andgcon v vertin g the alcohol tothe 1-halo -4,8,12-trimethyling said cyclohexanol to the cyclohexene,"5-1,

methyl-l- L2",6'-dimethylheptyll -*1- cyclohexene, I oxidizing saidcyclohexeneto the corresponding Y keto acid,4,8.12-trimethyl-0-ketotridecanoic acid.

tridecanei-byrneans of dry hydrogen-halide gas, I... "I

* 'LEE iRVmsmTH.

Patent No. 2,576,286.

czn'mmcam or conmzc'n'on.

I y 9 45 I LEE IRVIN SHI'IH? ET AL.

It is hereby certified that error'eppears iii the printed specificationrequiring correction as follows: Page 2, in the formula, uppermostcenter I portion thereof, for "H read --H and that the saidLettersvPatent should be read with this correction therein that the samemay conform to the record of the case ixi the Patent Office.

Signed and sealed this 16th day of October, A. D. 1915.

Leslie Frazer (Seal) v First Aa sistant Commissioner of'Patents.

